Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor.
Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor.
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DOI：
10.1016/j.ejpb.2014.12.016
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发表时间：
2015
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影响因子：
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通讯作者：
Kenji Tsukigawa;Hideaki Nakamura;Jun Fang;M. Otagiri;H. Maeda
中科院分区：
文献类型：
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作者：
Kenji Tsukigawa;Hideaki Nakamura;Jun Fang;M. Otagiri;H. Maeda
聚乙二醇化锌原卟啉（PEG-ZnPP）是一种水溶性血红素加氧酶-1抑制剂。在这项研究中，我们制备了两种类型的PEG-ZnPP缀合物，其中PEG和ZnPP之间具有不同的化学键，即，酯键和醚键，其中两种缀合物还含有酰胺键。这些键在体外和体内，特别是癌组织中的裂解能力，以及在细胞内摄取时，与缀合物的生物活性平行地进行了研究。每种缀合物显示出不同的裂解血浆酯酶和肿瘤蛋白酶，如通过HPLC分析所揭示的。含酯键的PEG-ZnPP（esPEG-ZnPP）比含醚键的PEG-ZnPP（etPEG-ZnPP）对PEG链的断裂更敏感。etPEG-ZnPP没有表现出PEG链的断裂，并且具有比esPEG-ZnPP更低的细胞内摄取和抗肿瘤活性。esPEG-ZnPP的降解似乎是由丝氨酸和半胱氨酸蛋白酶在肿瘤组织中促进的，而在除肝脏外的正常器官中则明显较慢。去聚乙二醇化产物如游离ZnPP具有比完整PEG-ZnPP更高的细胞内摄取。我们还研究了不同动物种属的血浆的水解裂解;小鼠血浆显示出最快的裂解，而人血浆显示出最慢的裂解。这些结果表明，酯连接的缀合物在肿瘤组织中比在正常组织中表现出更有效的PEG裂解和更高的活性成分从缀合物的产率。因此，预期酯连接的缀合物的更有效的细胞内摄取和因此改善的治疗效果具有良好的稳定性，特别是在人血液中。
Pegylated zinc protoporphyrin (PEG–ZnPP) is a water-soluble inhibitor of heme oxygenase-1. In this study, we prepared two types of PEG–ZnPP conjugates with different chemical bonds between PEG and ZnPP, i.e., ester bonds and ether bonds, where both conjugates also contain amide bonds. Cleavability of these bonds in vitro and in vivo, especially cancer tissue, and upon intracellular uptake, was investigated in parallel with biological activities of the conjugates. Each conjugate showed different cleavability by plasma esterases and tumor proteases, as revealed by HPLC analyses. PEG–ZnPP with ester bond (esPEG–ZnPP) was more sensitive than PEG–ZnPP with ether bond (etPEG–ZnPP) for cleavage of PEG chains. etPEG–ZnPP showed no cleavage of PEG chains and had lower intracellular uptake and antitumor activity than did esPEG–ZnPP. The degradation of esPEG–ZnPP appeared to be facilitated by both serine and cysteine proteases in tumor tissues, whereas it was significantly slower in normal organs except the liver. Depegylated products such as free ZnPP had higher intracellular uptake than did intact PEG–ZnPP. We also studied hydrolytic cleavage by blood plasma of different animal species; mouse plasma showed the fastest cleavage whereas human plasma showed the slowest. These results suggest that ester-linked conjugates manifest more efficient cleavage of PEG, and greater yield of the active principle from the conjugates in tumor tissues than in normal tissues. More efficient intracellular uptake and thus an improved therapeutic effect with ester-linked conjugates are thus anticipated with fain stability, particularly in human blood.